Infections during pregnancy can cause serious illness in pregnant women and their infants and can have an adverse impact on fetal growth and development. Influenza virus is an important respiratory pathogen that causes substantial burden of disease - including morbidity and mortality among pregnant women and young infants. Moreover, risk of influenza-related morbidity is higher in pregnant women in their second and third trimesters compared to non-pregnant and postpartum women. Vaccination is the most effective tool for preventing morbidity and mortality due to influenza. The potential impact of maternal influenza immunization on maternal and infant outcomes has important clinical and public health implications. Better understanding of infant effects of maternal influenza immunization could provide an important tool to combat respiratory disease in early infancy -not only in developing countries but also in many developed and middle income countries as there is no influenza vaccine currently approved for use in infants younger than 6 months. Therefore, we propose to conduct a randomized, double-blind, controlled, vaccine trial in Guatemala. The trial will be conducted at field sites in the departments (administrative units) of Quetzaltenango in western Guatemala and Santa Rosa in southern Guatemala. The enrollment will be conducted over three years;incorporating three influenza seasons. We will evaluate efficacy and safety of maternal immunization with inactivated influenza vaccine in a) pregnant women (before and after delivery) and b) their infants. The primary outcome of the proposed trial is laboratory (rRT-PCR) confirmed influenza infection in infants younger than 6 months. The secondary infant/fetus outcomes include clinical influenza-like illness, prematurity, birth weight, delivery complications, pneumonia and severe pneumonia (per WHO Integrated Management of Childhood Illness classification), hospitalizations due to severe acute respiratory illness, and adverse and severe adverse events. Moreover, secondary maternal outcomes include laboratory (rRT-PCR) confirmed influenza infection, clinical influenza-like illness, delivery complication, hospitalizations due to severe acute respiratory illness, and adverse and severe adverse events. We will also evaluate immunogenicity of the inactivated influenza vaccine by hemagglutination inhibition assay and microneutralization assay;and will estimate transplacental transfer of maternal influenza antibodies, infant antibody levels, and half life of antibodies acquired passively by infants. PUBLIC HEALTH RELEVANCE: Influenza infection during pregnancy can cause serious illness in pregnant women and their infants. Vaccination is the most effective tool for preventing morbidity and mortality due to influenza. However, currently there is no approved vaccine for infants younger than 6 months. Potential impact of maternal influenza immunization on maternal and infant outcomes has important clinical and public health implications. Therefore, we propose to conduct a randomized, double-blind, controlled, vaccine trial in Guatemala to evaluate the efficacy of influenza immunization in pregnancy for protecting mothers and their infants.